Social Avoidance Behavior Research Articles

Effect of Toll-like receptor 4 on depressive-like behaviors induced by chronic social defeat stress.

IntroductionA growing body of evidence suggests that stress is an important factor in depression, and pro‐inflammatory cytokines contribute to the occurrence and development of depression in both animal models and human patients. Toll‐like receptor 4 (TLR4) has been shown to be a key innate immune pattern recognition receptor involved in the regulation of stress responses and inflammation. However, the exact effects of TLR4 on depressive‐like behaviors induced by chronic social defeat stress (CSDS) are not known.MethodsIn this study, the effects of TLR4 on depressive‐like behaviors were investigated in an animal model of depression induced by CSDS. The depressive‐like behaviors were assessed by forced swimming test (FST), social interaction test (SIT), and light–dark box test (LDT). The protein expressions of TLR4 and tumor necrosis factor‐α (TNF‐α) in the hippocampus were measured using Western blotting.ResultsWe found that CSDS increased TLR4 protein levels in the hippocampus and induced behavioral despair in FST, social avoidance in SIT, and anxiety‐like behavior in LDT. Fluoxetine normalized the increased expression of TLR4 and reversed behavioral despair, social avoidance, as well as anxiety‐like behavior induced by CSDS. However, directly blocking TLR4, by using either TLR4 inhibitor TAK‐242 or knockout of TLR4, only inhibited behavioral despair, but not social avoidance or anxiety‐like behavior induced by CSDS.ConclusionsThese results demonstrate a specific modulating role of TLR4 in behavioral despair induced by CSDS and suggest that TAK‐242 may be a beneficial treatment for patients with behavioral despair.

Assessment of nest building and social interaction behavior in mice exposed to acute social defeat stress using a three-dimensional depth camera.

Nest building is an instinctive behavior toward protection from predators, body temperature regulation, and courtship. Previously, we discovered that acute and chronic social defeat stress suppresses the onset of nest-building behavior in male mice (C57BL/6J). Here, we analyzed nest building and other behavioral deficits induced by acute social defeat stress (ASDS). We utilized a customized cage and specifically developed observational programs for nest building, social avoidance, and other behaviors using an infrared depth camera to acquire three-dimensional (3D) data of animal behavior (Negura system). We determined the volume of nesting materials from these 3D depth images. Mice exposed to ASDS showed increased spontaneous activities, decreased rearing, and delayed nest building; however, nest-building activity was gradually recovered during the dark period of the 24hr observation interval. At the endpoint following 24hr, the ASDS and control groups showed no differences in nest volumes. Furthermore, we observed the time courses of both nest building and social avoidance behaviors and their relationship using the Negura system. Our data demonstrated a weak positive correlation between nest-building delay and social avoidance in ASDS mice. The Negura system can observe various behaviors that reflect the effects of social defeat stress.

Social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics in the laboratory.

Adult male tree shrews vigorously defend against intruding male conspecifics. However, the characteristics of social behavior have not been entirely explored in these males. In this study, male wild-type tree shrews (Tupaia belangeri chinensis) and C57BL/6J mice were first allowed to familiarize themselves with an open-field apparatus. The tree shrews exhibited a short duration of movement (moving) in the novel environment, whereas the mice exhibited a long duration of movement. In the 30 min social preference-avoidance test, target animals significantly decreased the time spent by the experimental tree shrews in the social interaction (SI) zone, whereas experimental male mice exhibited the opposite. In addition, experimental tree shrews displayed a significantly longer latency to enter the SI zone in the second 15 min session (target-present) than in the first 15 min session (target-absent), which was different from that found in mice. Distinct behavioral patterns in response to a conspecific male were also observed in male tree shrews and mice in the first, second, and third 5 min periods. Thus, social behaviors in tree shrews and mice appeared to be time dependent. In summary, our study provides results of a modified social preference-avoidance test designed for the assessment of social behavior in tree shrews. Our findings demonstrate the existence of social avoidance behavior in male tree shrews and prosocial behavior in male mice toward unfamiliar conspecifics. The tree shrew may be a new animal model, which differs from mice, for the study of social avoidance and prosocial behaviors.

New Gambling Task Reveals an Atypical Relation Between Social Anxiety and Social Avoidance in Schizophrenia

Abstract A core symptom of schizophrenia is a deficit in social cognition. Furthermore, many patients suffer from relevant social anxiety. How social anxiety relates to social avoidance in schizophrenia is, however, still unclear. To address this question empirically, 30 participants with schizophrenia were compared to individually matched controls in a recently developed experimental task. In each trial, participants chose between a monetary gamble with a human partner providing social feedback and a defined monetary amount that varied across trials. The tendency to avoid the interaction under acceptance of monetary loss served as a measure of social avoidance. Patients showed higher levels of social anxiety assessed using the Liebowitz Social Anxiety Scale (LSAS) than controls, took longer to decide whether to engage in the social interaction and rated social feedback as less intense. Despite making rational decisions, patients surprisingly showed no social avoidance. We assume that the lack of experimentally induced social avoidance in contrast to the well-known social avoidance behavior in everyday life, also reflected by elevated self-rated LSAS scores, was due to a partial compensation of delayed social information processing in the absence of the time constraints in our task. This additional time may have allowed rational decisions and masked potential social avoidance behavior. We conclude that social anxiety in schizophrenia may have different characteristics than in individuals without schizophrenia, namely avoidance of negative feedback caused by prolonged social processing instead of fear of supposed negative feedback. Treatment strategies for social anxiety in schizophrenia may benefit from considering these differences.

Перевод, апробация и первичная психометрическая оценка опросника тревоги на рабочем месте Б. Мушалла и М. Линдена (JAS)

The paper presents the results of approbation of the Russian-language version of the Job Anxiety Scale (JAS) by B. Mushalla and M. Linden, based on a differentiated clinical approach to anxiety states during work. The 70-item scale was translated into Russian and tested in a sample of 410 subjects, who were professionals in various fields. The exploratory factor analysis procedure identified a five-factor structure that was different from the original one. The factors were named as follows: 1) Discomfort, tension, and anxiety at work with the conviction of its harmfulness; 2) Social anxiety and avoidant behavior in the workplace; 3) Experiencing injustice and exploitation in the workplace; 4) Anxiety for the preservation of the workplace and the future; 5) Cognitions about one’s inefficiency. High reliability of the Russian version of JAS has been established. The Cronbach’s α coefficient for the entire scale was 0.973; the Gutmann split-half coefficient was 0.945. There were multiple correlations between the JAS scores and the symptoms of mental disorders assessed by the SCL-90-R, which can be considered as evidence of the external validity of the scale.

Effects of 17β-trenbolone exposure on sex hormone synthesis and social behaviours in adolescent mice.

17β-Trenbolone (17β-TBOH) is an endocrine disruptor that has been widely reported in aquatic organisms. However, little is known about the effect of 17β-TBOH on mammals, particularly on the development of adolescents. Through a series of behavioural experiments, exposure to at 80μgkg -1d -1 and 800μgkg -1d -1 17β-TBOH during puberty (from PND 28 to 56, male mice) increased anxiety-like behaviours. Exposure to the low dose of 80μgkg -1d -1 resulted in a clear social avoidance behaviour in mice. The two doses affected testicular development and endogenous androgen synthesis in male mice. In addition, 17β-TBOH exposure altered the differentiation of oligodendrocytes and the formation of the myelin sheath in the medial prefrontal cortex (mPFC). These results reveal the effects of 17β-TBOH on the behaviours, gonadal and neurodevelopment of adolescent mammals. In addition, the inhibition of the secretion of endogenous hormones and decrease in the formation of the myelin sheath in mPFC may be associated with the 17β-TBOH-induced behavioural changes in mice.

Effects of social defeat stress and fluoxetine treatment on neurogenesis and behavior in mice that lack zinc transporter 3 (ZnT3) and vesicular zinc.

Depression is a leading cause of disability worldwide, in part because the available treatments are inadequate and do not work for many people. The neurobiology of depression, and the mechanism of action of common antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), is not well understood. One mechanism thought to underlie the effects of these drugs is upregulation of adult hippocampal neurogenesis. Evidence indicates that vesicular zinc is required for modulation of adult hippocampal neurogenesis, at least under some circumstances. Vesicular zinc refers to zinc that is stored in the synaptic vesicles of certain neurons, including in the hippocampus, and released in response to neuronal activity. It can be eliminated from the brain by deletion of zinc transporter 3 (ZnT3), as is the case in ZnT3 knockout mice. Here, we examined the effects of repeated social defeat stress and subsequent chronic treatment with the SSRI fluoxetine on behavior and neurogenesis in ZnT3 knockout mice. We hypothesized that fluoxetine treatment would increase neurogenesis and reverse stress-induced behavioral symptoms in wild type, but not ZnT3 knockout, mice. As anticipated, stress induced persistent depression-like effects, including social avoidance and anxiety-like behavior. Fluoxetine decreased social avoidance, though the effect was not specific to the stressed mice, but did not affect anxiety-like behavior. Surprisingly, stress increased the survival of neurons born 1 day after the last episode of defeat stress. Fluoxetine treatment also increased cell survival, particularly in wild type mice, though it did not affect proliferation. Our results did not support our hypothesis that vesicular zinc is required for the behavioral benefits of fluoxetine treatment. As to whether vesicular zinc is required for the neurogenic effects of fluoxetine, our results were inconclusive, warranting further investigation into the role of vesicular zinc in adult hippocampal neurogenesis.

A clinical staging approach to improving diagnostics in anxiety disorders: Is it the way to go?

Clinical staging is a paradigm in which stages of disease progression are identified; these, in turn, have prognostic value. A staging model that enables the prediction of long-term course in anxiety disorders is currently unavailable but much needed as course trajectories are highly heterogenic. This study therefore tailored a heuristic staging model to anxiety disorders and assessed its validity. A clinical staging model was tailored to anxiety disorders, distinguishing nine stages of disease progression varying from subclinical stages (0, 1A, 1B) to clinical stages (2A-4B). At-risk subjects and subjects with anxiety disorders (n = 2352) from the longitudinal Netherlands Study of Depression and Anxiety were assigned to these nine stages. The model's validity was assessed by comparing baseline (construct validity) and 2-year, 4-year and 6-year follow-up (predictive validity) differences in anxiety severity measures across stages. Differences in depression severity and disability were assessed as secondary outcome measures. Results showed that the anxiety disorder staging model has construct and predictive validity. At baseline, differences in anxiety severity, social avoidance behaviors, agoraphobic avoidance behaviors, worrying, depressive symptoms and levels of disability existed across all stages (all p-values < 0.001). Over time, these differences between stages remained present until the 6-year follow-up. Differences across stages followed a linear trend in all analyses: higher stages were characterized by the worst outcomes. Regarding the stages, subjects with psychiatric comorbidity (stages 2B, 3B, 4B) showed a deteriorated course compared with those without comorbidity (stages 2A, 3A, 4A). A clinical staging tool would be useful in clinical practice to predict disease course in anxiety disorders.

Korean Red Ginseng reduces chronic social defeat stress-induced mood disorders via N-methyl-D-aspartate receptor modulation in mice

BackgroundA chronic social defeat stress (CSDS) model has been proposed as relevant to stress-induced behavioral change in humans. In this study, we examined the effect of Korean Red Ginseng (KRG) on CSDS-induced mood disorders and protein expression in an animal model. MethodsTo evaluate the effect of KRG on social defeat stress, test mice were exposed in the resident aggressor's home cage compartment for 14 days beginning 1 h after KRG treatment (10, 20, and 40 mg/kg, per oral (p.o.)). After the exposure, behavioral tests to measure anxiety, social interaction, and depression-like behavior were performed. To investigate the underlying mechanism, N-methyl-D-aspartate receptor expression levels in CSDS-induced mice were evaluated using Western blot analysis. ResultsCSDS induced anxiety-like behaviors by decreasing central activity in the open-field test and open-arm approach in the elevated plus maze test and led to social avoidance behavior in the social interaction test. CSDS mice showed upregulated NR1, NR2A, and NR2B expression in the hippocampus. KRG 20 and 40 mg/kg ameliorated anxiety-like activities and KRG 20 mg/kg alleviated social avoidance by decreasing time in the corner zone. KRG treatment recovered CSDS-induced NR1, NR2A, and NR2B protein levels in the hippocampus. ConclusionThese results indicate that KRG has a therapeutic effect on CSDS-induced mood disorder by alleviating N-methyl-D-aspartate receptor overexpression in the hippocampus.

Antidepressant effect of the translocator protein antagonist ONO-2952 on mouse behaviors under chronic social defeat stress

In preclinical models, it has been reported that social defeat stress activates microglial cells in the CNS. Translocator protein 18 kDa (TSPO) is a mitochondrial protein expressed on microglia in the CNS that has been proposed to be a useful biomarker for brain injury and inflammation. We hypothesized that a TSPO antagonist, ONO-2952, would inhibit the neuroinflammation induced by microglial hyperactivation and associated depressive-like behaviors. An in vitro analysis showed that ONO-2952 suppressed the release of pro-inflammatory cytokines and mitochondrial reactive oxygen species in cultured microglia stimulated by lipopolysaccharide. In mice submitted to chronic social defeat stress, microglia predominantly expressed TSPO in limbic areas implicated in depressive-like behaviors, including the amygdala, ventral hippocampus and nucleus accumbens, in which an increase in the production of pro-inflammatory cytokines in vivo were associated. Treating animals with ONO-2952 during chronic social defeat stress ameliorated impairments in social avoidance and anxiety-like behaviors and suppressed pro-inflammatory cytokine production, suggesting that ONO-2952 exerted an anti-stress effect in this animal model of depression. Thus, targeting TSPO as a candidate for the development of antidepressants that reduce susceptibility to chronic stress could pave the way toward therapeutic interventions for relapse prophylaxis in depression.

Influence of aging on the behavioral phenotypes of C57BL/6J mice after social defeat.

Depression and anxiety are common psychiatric disorders that can occur throughout an individual’s lifetime. Numerous pathways underlying the onset of these diseases have been identified in rodents using a social defeat stress protocol, whereby socially defeated individuals exhibit depression- and/or anxiety-like phenotypes that typically manifest as social avoidance behavior. However, most studies in this field have been conducted using young adult mice; therefore, information about social defeat stress-related behavioral phenotypes in older mice is limited. In this study, we exposed groups of young adult (8–16 weeks old) and aged (24 months old) C57BL/6J mice to mild social defeat stress by challenging them with aggressive CD1 mice while restricting the intensity of aggression to protect the animals from severe injuries. We then identified stress-induced behavioral changes and compared their expression between the age groups and with a non-defeated (non-stressed) control group. We found that the stressed mice in both age groups exhibited similar reduced social interactions that were indicative of increased social avoidance behavior. Moreover, unlike the young stressed and control groups, only the aged stressed group showed a reduced preference for sucrose, which was correlated with social avoidance behavior. Also, the aged stressed mice exhibited an attenuated defeat-induced increase in water intake. These findings reveal that aging alters behavioral phenotypes after social defeat and that the hedonic behavior of aged mice is more vulnerable to social defeat compared with younger mice.

A novel eye-tracking paradigm for indexing social avoidance-related behavior in fragile X syndrome.

Fragile X syndrome (FXS) is characterized by hallmark features of gaze avoidance, reduced social approach, and social anxiety. The development of therapeutics to manage these symptoms has been hindered, in part, by the lack of sensitive outcome measures. This study investigated the utility of a novel eye-tracking paradigm for indexing social avoidance-related phenotypes. Adolescent/young adult-aged males with FXS (n = 24) and typical development (n = 23) participated in the study. Participants viewed faces displaying direct or averted gaze and the first fixation duration on the eyes was recorded as an index of initial stimulus registration. Fixation durations did not differ across the direction of gaze conditions in either group, although the control group showed longer initial fixations on the eyes relative to the FXS group. Shorter initial fixation on averted gaze in males with FXS was a robust predictor of the severity of their social avoidance behavior exhibited during a social greeting context, whereas parent-reported social avoidance symptoms were not related to performance in the semi-naturalistic context. This eye-tracking paradigm may represent a promising outcome measure for FXS clinical trials because it provides a quantitative index that closely maps onto core social avoidance phenotypes of FXS, can be completed in less than 20 min, and is suitable for use with individuals with low IQ.

Improvement of PTSD-like behavior by the forgetting effect of hippocampal neurogenesis enhancer memantine in a social defeat stress paradigm

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Recent studies have shown that the forgetting of contextual fear memory is promoted via increased adult hippocampal neurogenesis induced by neurogenesis enhancers, such as memantine (MEM) and exercise, raising the possibility that neurogenesis enhancers improve PTSD by facilitating the forgetting of traumatic memory. On the other hand, repeated exposure to social defeat (SD) stress by aggressor mice induces social avoidance behavior to the aggressor and chronic anxiety-like behavior. In this study, we assumed this SD stress paradigm as a PTSD-like model and examined the effects of treatment with neurogenesis enhancer MEM on SD stress-induced PTSD-like behavior. Male C57BL/6 mice received SD stress for 10 consecutive days and were assessed for social avoidance memory to the aggressor (memory of aggressor mice) and anxiety-like behavior using social interaction and elevated zero maze tasks. Consistent with previous studies, SD mice formed social avoidance memory and exhibited increased anxiety-like behavior. Importantly, subsequent MEM treatment (once a week for 4 weeks) significantly reduced social avoidance behavior, suggesting that MEM-treated SD mice showed forgetting of social avoidance memory. Interestingly, MEM-treated SD mice showed comparable anxiety-like behavior with control mice that were not exposed to SD stress. Moreover, MEM-treated SD mice showed no reinstatement of social avoidance memory following single re-exposure to the aggressor. Our findings suggest that neurogenesis enhancer not only enhanced the forgetting of traumatic memory but also improved PTSD (anxiety)-like behavior.

Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling

How individuals respond to chronic stress varies. Susceptible individuals ultimately develop depression; whereas resilient individuals live normally. In this study, our objective was to examine the effect of branched-chain amino acids (BCAA), commonly used by athletes, on susceptibility to stress. Male C57BL/6 mice were subjected to daily defeat sessions by a CD1 aggressor, for 10 days. On day11, the behavior of mice was assessed using the social interaction test, elevated plus maze and open field. Mice received the BCAA leucine, isoleucine or valine before each defeat session. Furthermore, we examined whether BCAA regulate brain derived neurotrophic factor (BDNF) signaling by using a brain-permeable tropomyosin receptor kinase B (TRKB) inhibitor, ANA-12. We also tested the effect of voluntary exercise and high protein diets on susceptibility to stress. Mice exposed to chronic stress displayed increased susceptibility and social avoidance. BCAA promoted resilience to chronic stress, rescued social avoidance behaviors and increased hippocampal BDNF levels and TRKB activation. Inhibition of TRKB signaling abolished the ability of BCAA to promote resilience to stress and to rescue social avoidance. Interestingly, we found that BCAA activate the exercise-regulated PGC1a/FNDC5 pathway known to induce hippocampal BDNF signaling. Although both voluntary exercise and BCAA promoted resilience to stress, combining them did not yield synergistic effects confirming that they affect similar pathways. We also discovered that high protein diets mimic the effect of BCAA by rescuing social deficits induced by chronic stress and increase Bdnf expression in the hippocampus. Our data indicate that BCAA, exercise and high protein diets rescue susceptibility to stress by activating the hippocampal BDNF/TRKB signaling.

Infant Social Avoidance Predicts Autism but Not Anxiety in Fragile X Syndrome.

Objective: Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and anxiety are three of the most common childhood psychiatric disorders. Early trajectories of social avoidance have been linked with these psychiatric disorders in previous studies, but it remains unclear how social avoidance differentially predicts comorbid disorders in a high-risk genetic subgroup. Here, we delineate the association between trajectories of social avoidance from infancy and subsequent ASD, ADHD, and anxiety outcomes at preschool in children with fragile X syndrome (FXS), a well-characterized single-gene disorder highly associated with social avoidance as well as elevated rates of ASD, ADHD, and anxiety.Method: Males with FXS (n = 78) aged 4–62 months participated in a longitudinal study resulting in 201 assessments. The Social Avoidance Scale (SAS) documented socially avoidant behaviors from infancy in three domains—physical movement, facial expression, and eye contact during both the first minute and the last hour of an interaction. ASD, ADHD, and anxiety symptom outcomes at preschool were measured via parent-report questionnaires.Results: Increased social avoidance across infancy and preschool predicted elevated ASD symptom severity but reduced ADHD and anxiety symptom severity in males with FXS.Conclusion: ASD, ADHD, and anxiety symptoms relate inconsistently to social avoidance behaviors, providing new insight toward the debate of independence or overlap among these disorders in FXS and other disorders (i.e., ASD). The results suggest that the nuanced profile of the developmental and temporal aspects of social avoidance may inform more the accuracy of differential diagnoses of comorbid psychiatric disorders in FXS.

Presence of the pregnant partner regulates microRNA-30a and BDNF levels and protects male mice from social defeat-induced abnormal behaviors

Consolation behavior within close social bonds can alleviate the negative effects of stressful events on individuals. Due to the lack of animal models, however, its underlying mechanisms remain poorly explored. Moreover, most social support effects are exerted through grooming or consolation behavior from close social bonds, whether pure companionship without physical interaction exert effects still remains unknown. Here, we report that among the most widely used laboratory mouse, social avoidance and anxiety-related behaviors induced by chronic social defeat stress (CSDS) were alleviated by the presence of their pregnant partner without body contact during the stress process, whereas non-pregnant females did not afford similar protective effect to the male partner. The levels of BDNF, together with its primary transcripts, were down-regulated in the hippocampus of male mice with CSDS and these decreases were ameliorated by the presence of their pregnant partners. Furthermore, miR-30a negatively regulated BDNF expression and the regulation of miR-30a was implicated in the supporting effect on the male mice experiencing CSDS. The identification of psychological protective effects in a primary model organism and its underlying mechanism would promote our understanding how people cope with stress-induced psychiatric disorders independent of anti-depressant drugs and facilitate investigation of the molecular mechanisms of enduring social bonds in humans.This article is part of the Special Issue entitled ‘The neuropharmacology of social behavior: from bench to bedside’.

The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function.

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

Pain-related avoidance and endurance behaviour in migraine: an observational study

BackgroundThe role of avoidance and endurance behaviour is well established in chronic musculoskeletal pain, but less is known about its significance in migraine.MethodsThe Avoidance-Endurance Questionnaire behavioural subscales, the Pain Disability Index (PDI), the Migraine Disability Assessment Scale (MIDAS) and the Hospital Anxiety and Depression Scale (HADS) were obtained from 128 migraine patients (90 episodic, 38 chronic). Sixty nine of them were re-evaluated after 3–6 months.ResultsAt baseline, there were positive relations between avoidance (especially social avoidance behaviour) and pain-related disability as assessed by the PDI (Wald χ2 [1] = 32.301, p < 0.001) and the MIDAS (Wald χ2 [1] = 14.387, p < 0.001). A negative relation of endurance behaviour with PDI scores did not survive multiple regression analysis. In addition, there was a positive relation of social avoidance with the HADS depression score (Wald χ2 [1] = 3.938, p = 0.047) and a negative relation of endurance (especially the humour-distraction subscale) with the HADS anxiety score (Wald χ2 [1] = 6.163, p = 0.013). Neither avoidance nor endurance were related to headache intensity or frequency, or to a diagnosis of episodic vs. chronic migraine. 3–6 months after treatment at our headache centre, headache frequency, intensity and pain-related disability were significantly improved (all p < 0.01) while avoidance and endurance were unchanged.ConclusionsThis indicates that improvement in headache frequency and disability can be achieved in the absence of changes in avoidance or endurance behaviour. However, because of its significant link to headache-related disability, avoidance behaviour (especially social avoidance) should be investigated as a potential additional target of migraine therapy.

Sufficient intake of high-fat food attenuates stress-induced social avoidance behavior

AimsPsychosocial stress is a form of mental stress associated with human relationships that underlies the pathogenesis of mental disorders such as depression. Previous studies have suggested that intake of energy-dense foods, also known as “palatable foods,” can relieve psychosocial stress. However, it remains unclear whether the volume of palatable food affects abnormal behavior induced by psychosocial stress. In the present study, we aimed to determine whether levels of high-fat food intake significantly influence psychosocial stress using the social-defeat stress (SDS) paradigm. Main methodsMice subjected to SDS ate either a high-fat or normal chow diet for 10 days. Behavioral tests were conducted following the completion of the SDS paradigm. The hypothalamus, liver, and blood were examined post-mortem. Key findingsMice with sufficient intake of high-fat chow immediately following exposure to SDS did not exhibit social avoidance behavior, suggesting that a high-fat diet may improve social behavior. However, inadequate intake of high-fat food, which did not alter cholesterol metabolism or hypothalamic-pituitary-adrenal axis activity, was not associated with such benefits, instead increased anxiety-like behavior. SignificanceThe results of the present study demonstrate that eating a high-fat diet may attenuate stress, but that this benefit disappears with insufficient intake of high-fat foods. The benefits of a high-fat diet under SDS may be related to cholesterol metabolism in the liver.

Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases.

Chronic stress promotes depression in some individuals, but has no effect in others. Susceptible individuals exhibit social avoidance and anxious behavior and ultimately develop depression, whereas resilient individuals live normally. Exercise counteracts the effects of stress. Our objective was to examine whether lactate, a metabolite produced during exercise and known to reproduce specific brain exercise-related changes, promotes resilience to stress and acts as an antidepressant. To determine whether lactate promotes resilience to stress, male C57BL/6 mice experienced daily defeat by a CD-1 aggressor, for 10 days. On the 11th day, mice were subjected to behavioral tests. Mice received lactate before each defeat session. When compared with control mice, mice exposed to stress displayed increased susceptibility, social avoidance and anxiety. Lactate promoted resilience to stress and rescued social avoidance and anxiety by restoring hippocampal class I histone deacetylase (HDAC) levels and activity, specifically HDAC2/3. To determine whether lactate is an antidepressant, mice only received lactate from days 12-25 and a second set of behavioral tests was conducted on day 26. In this paradigm, we examined whether lactate functions by regulating HDACs using co-treatment with CI-994, a brain-permeable class I HDAC inhibitor. When administered after the establishment of depression, lactate behaved as antidepressant. In this paradigm, lactate regulated HDAC5 and not HDAC2/3 levels. On the contrary, HDAC2/3 inhibition was antidepressant-like. This indicates that lactate mimics exercise's effects and rescues susceptibility to stress by modulating HDAC2/3 activity and suggests that HDAC2/3 play opposite roles before and after establishment of susceptibility to stress.